title: Effect of Irbesartan treatment on plasma and urinary markers of protein damage in patients with type 2 diabetes and microalbuminuria.
abstract: The aim of this study was to assess the effect of the angiotensin II receptor blocker Irbesartan on protein damage by glycation, oxidation and nitration in patients with type 2 diabetes and microalbuminuria. In a double-masked randomised crossover trial of 52 hypertensive type 2 diabetic patients, antihypertensive treatment was replaced with bendroflumethiazide. After 2-months wash-out, patients were treated randomly with Irbesartan 300, 600, and 900 mg o.d., each dose for 2 months in a three-way crossover study. Glycation, oxidation and nitration adduct residues in plasma protein and related urinary free adducts were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Treatment with Irbesartan decreased urinary excretion of advanced glycation endproducts (AGEs)--methylglyoxal- and glyoxal-derived hydroimidazolones, MG-H1 and G-H1. Urinary AGEs were decreased by 30-32%. In plasma protein, treatment with Irbesartan increased content of glycation adducts Nε-fructosyl-lysine, AGEs Nε-carboxymethyl-lysine, Nε-carboxyethyl-lysine and pentosidine, and also increased content of oxidation markers N-formylkynurenine and dityrosine. This was attributed to decreased clearance of plasma protein modified by Nε-fructosyl-lysine and oxidative markers through the glomerular filter tightened by Irbesartan treatment. Treatment of patients with type 2 diabetes with Irbesartan decreased urinary excretion of MG-H1, G-H1 and 3-NT, which may result from decreased exposure to these AGEs. This is likely achieved by blocking angiotensin II signalling and related down-regulation of glyoxalase 1 and may contribute to health benefits of Irbesartan therapy.
authors.affiliation: Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry, CV2 2DX, UK.
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.forename: Antonysunil
authors.initials: A
authors.lastname: Adaikalakoteswari
authors.forename: Kasper
authors.initials: K
authors.lastname: Rossing
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
mesh_terms: D000419:Albuminuria / Q000188:drug therapy; D000596:Amino Acids / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001539:Bendroflumethiazide / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D003928:Diabetic Nephropathies / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood / Q000652:urine*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D000077405:Irbesartan; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000596:Amino Acids; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D015415:Biomarkers; D001713:Biphenyl Compounds; D017127:Glycation End Products, Advanced; D013777:Tetrazoles; C002744:3-nitrotyrosine; D014443:Tyrosine; D001539:Bendroflumethiazide; D000077405:Irbesartan